This invention pertains generally to valency molecules. The invention also relates to the field of valency platform molecules which act as scaffolds to which one or more molecules may be covalently tethered to form a conjugate. More particularly, the present invention pertains to valency molecules which comprise a carbamate linkage (i.e., xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94N less than ). In one aspect, the present invention pertains to valency platforms comprising carbamate linkages, which molecules have the structure of any one of Formulae I, II, or III, shown in FIG. 1. In one aspect, the present invention pertains to valency platforms comprising carbamate linkages, which molecules have the structure of any one of Formulae IV, V, or VI, shown in FIG. 8. The present invention also pertains to methods of preparing such valency molecules, conjugates comprising such valency molecules, and methods of preparing such conjugates.
A xe2x80x9cvalency platformxe2x80x9d is a molecule with one or more (and typically multiple) attachment sites which can be used to covalently attach biologically active molecules of interest to a common scaffold. The attachment of biologically active molecules to a common scaffold provides multivalent conjugates in which multiple copies of the biologically active molecule are covalently linked to the same platform. A xe2x80x9cdefinedxe2x80x9d or xe2x80x9cchemically definedxe2x80x9d valency platform is a platform with defined structure, thus a defined number of attachment points and a defined valency. A defined valency platform conjugate is a conjugate with defined structure and has a defined number of attached biologically active compounds. Examples of biologically active molecules include oligonucleotides, peptides, polypeptides, proteins, antibodies, saccharides, polysaccharides, epitopes, mimotopes, drugs, and the like. In general, biologically active compounds interact specifically with proteinaceous receptors.
Certain classes of chemically defined valency platforms, methods for their preparation, conjugates comprising them, and methods for the preparation of such conjugates, have been described in the U.S. Pat. Nos. 5,162,515; 5,391,785; 5,276,013; 5,786,512; 5,726,329; 5,268,454; 5,552,391; 5,606,047; and 5,663,395.
The valency platforms of the present invention reflect a new class of valency platforms which comprise a carbamate linkage, as shown, for example, in Formulae I, II, and III in FIG. 1 and in Formulae IV, V, and VI in FIG. 8.
One aspect of the present invention pertains to a valency platform compound having the structure of one of the following formulae: 
wherein:
n is a positive integer from 1 to 10;
y1, y2, and y3 are independently 1 or 2;
J independently denotes either an oxygen atom or a covalent bond;
RC is selected from the group consisting of:
hydrocarbyl groups having from 1 to 20 carbon atoms;
organic groups consisting only of carbon, oxygen, and hydrogen atoms, and having from 1 to 20 carbon atoms;
organic groups consisting only of carbon, oxygen, nitrogen, and hydrogen atoms, and having from 1 to 20 carbon atoms;
organic groups consisting only of carbon, oxygen, sulfur, and hydrogen atoms, and having from 1 to 20 carbon atoms;
each G1, G2, and G3 is independently selected from the group consisting of:
hydrocarbyl groups having from 1 to 20 carbon atoms;
organic groups consisting only of carbon, oxygen, and hydrogen atoms, and having from 1 to 20 carbon atoms;
organic groups consisting only of carbon, oxygen, nitrogen, and hydrogen atoms, and having from 1 to 20 carbon atoms;
each RN is independently selected from the group consisting of: hydrogen;
linear or branched alkyl groups having from 1 to 15 carbon atoms;
alkyl groups comprising an alicyclic structure and having from 1 to 15 carbon atoms;
aromatic groups having from 6 to 20 carbon atoms;
heteroaromatic groups having from 3 to 20 carbon atoms;
each Z is independently selected from the group consisting of:
xe2x80x94H
xe2x80x94C(xe2x95x90O)ORCARB 
xe2x80x94C(xe2x95x90O)RESTER 
xe2x80x94C(xe2x95x90O)NRARB 
wherein:
each RCARB is organic groups comprising from 1 to about 20 carbon atoms;
each RESTER is organic groups comprising from 1 to about 20 carbon atoms;
each group xe2x80x94NRARB is independently selected from the group consisting of:
xe2x80x94NH2 
xe2x80x94NHRA 
xe2x80x94NRARB 
xe2x80x94NRAB 
wherein each monovalent RA and RB and each divalent RAB is independently an organic group comprising from 1 to 20 carbon atoms, and further comprising a reactive conjugating functional group.
In one embodiment, said compound has the structure of Formula I. In one embodiment, said compound has the structure of Formula II. In one embodiment, said compound has the structure of Formula III. In one embodiment, said compound has the structure of Formula IV. In one embodiment, n is a positive integer from 2 to 4. In one embodiment, y1, y2, and y3 are each 2. In one embodiment, J is an oxygen atom. In one embodiment, J is a covalent bond. In one embodiment, RC is selected from the group consisting of hydrocarbyl groups having from 1 to 20 carbon atoms. In one embodiment, RC is selected from the group consisting of: 
In one embodiment, RC is selected from the group consisting of organic groups consisting only of carbon, oxygen, and hydrogen atoms, and having from 1 to 20 carbon atoms. In one embodiment, RC is: 
wherein p is a positive integer from 2 to 20. In one embodiment, each G1, G2, and G3 is independently selected from the group consisting of hydrocarbyl groups having from 1 to 20 carbon atoms. In one embodiment, each G1, G2, and G3 is xe2x80x94(CH2)qxe2x80x94 wherein q is a positive integer from 1 to 20. In one embodiment, each G1, G2, and G3 is independently selected from the group consisting of organic groups consisting only of carbon, oxygen, and hydrogen atoms, and having from 1 to 20 carbon atoms. In one embodiment, each G1, G2, and G3 is: 
wherein p is a positive integer from 2 to 20. In one embodiment, RN is independently selected from the group consisting of xe2x80x94H, xe2x80x94CH3, and xe2x80x94CH2CH3. In one embodiment, each group xe2x80x94NRARB is independently selected from the group consisting of: 
Another aspect of the present invention pertains to a valency platform compound having the structure of one of the following formulae: 
wherein:
n is a positive integer from 1 to 10;
y1, y2, and y3 are independently a positive integer from 1 to 10;
J independently denotes either an oxygen atom or a covalent bond;
RC is selected from the group consisting of:
hydrocarbyl groups having from 1 to 20 carbon atoms;
organic groups consisting only of carbon, oxygen, and hydrogen atoms, and having from 1 to 20 carbon atoms;
organic groups consisting only of carbon, oxygen, nitrogen, and hydrogen atoms, and having from 1 to 20 carbon atoms;
organic groups consisting only of carbon, oxygen, sulfur, and hydrogen atoms, and having from 1 to 20 carbon atoms;
each G1, G2, and G3 is independently selected from the group consisting of:
hydrocarbyl groups having from 1 to 20 carbon atoms;
organic groups consisting only of carbon, oxygen, and hydrogen atoms, and having from 1 to 20 carbon atoms;
organic groups consisting only of carbon, oxygen, nitrogen, and hydrogen atoms, and having from 1 to 20 carbon atoms;
each RN is independently selected from the group consisting of:
hydrogen;
linear or branched alkyl groups having from 1 to 15 carbon atoms;
alkyl groups comprising an alicyclic structure and having from 1 to 15 carbon atoms;
aromatic groups having from 6 to 20 carbon atoms;
heteroaromatic groups having from 3 to 20 carbon atoms;
each Z is independently selected from the group consisting of:
xe2x80x94H
xe2x80x94C(xe2x95x90O)ORCARB 
xe2x80x94C(xe2x95x90O)RESTER 
xe2x80x94C(xe2x95x90O)NRARB 
wherein:
each RCARB is organic groups comprising from 1 to about 20 carbon atoms;
each RESTER is organic groups comprising from 1 to about 20 carbon atoms;
each group xe2x80x94NRARB is independently selected from the group consisting of:
xe2x80x94NH2 
xe2x80x94NHRA 
xe2x80x94NRARB 
xe2x80x94NRAB 
wherein each monovalent RA and RB and each divalent RAB is independently an organic group comprising from 1 to 20 carbon atoms, and further comprising a reactive conjugating functional group.
In one embodiment, said compound has the structure of Formula V. In one embodiment, said compound has the structure of Formula VI. In one embodiment, said compound has the structure of Formula VII. In one embodiment, n is a positive integer from 2 to 4. In one embodiment, y1, y2, and y3 are each 2. In one embodiment, J is an oxygen atom. In one embodiment, J is a covalent bond. In one embodiment, RC is selected from the group consisting of hydrocarbyl groups having from 1 to 20 carbon atoms. In one embodiment, RC is selected from the group consisting of: 
In one embodiment, RC is selected from the group consisting of organic groups consisting only of carbon, oxygen, and hydrogen atoms, and having from 1 to 20 carbon atoms. In one embodiment, RC is: 
wherein p is a positive integer from 2 to 20. In one embodiment, each G1, G2, and G3 is independently selected from the group consisting of hydrocarbyl groups having from 1 to 20 carbon atoms. In one embodiment, each G1, G2, and G3 is selected from the group consisting of: 
In one embodiment, each G1, G2, and G3 is independently selected from the group consisting of organic groups consisting only of carbon, oxygen, and hydrogen atoms, and having from 1 to 20 carbon atoms. In one embodiment, each RN is independently selected from the group consisting of xe2x80x94H, xe2x80x94CH3, and xe2x80x94CH2CH3. In one embodiment, each group xe2x80x94NRARB is independently selected from the group consisting of: 
Another aspect of the present invention pertains to methods of preparing a valency platform compound, as described herein.
Another aspect of the present invention pertains to a conjugate comprising a valency platform compound, as described herein, covalently linked to one or more biologically active molecules. In one embodiment, said biologically active molecules are selected from the group consisting of: oligonucleotides, peptides, polypeptides, proteins, antibodies, saccharides, polysaccharides, epitopes, mimotopes, and drugs.
Another aspect of the present invention pertains to methods of preparing conjugates, as described herein.
As will be appreciated by one of skill in the art, features of one aspect or embodiment of the invention are also applicable to other aspects or embodiments of the invention.